1. Field of the Invention (Technical Field)
The present invention relates to small ring-core molecules characterized in that they may be employed for the treatment of sexual dysfunction in mammals, including both male erectile dysfunction and female sexual dysfunction in humans, without modulating feeding behavior in mammals and without being substantially specific for any melanocortin receptor, including not substantially inhibiting binding at MC4-R, and methods for the treatment of sexual dysfunction in mammals without modulation of feeding behavior or eliciting or causing other responses characteristic of MC4-R specific molecules.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of tissues.
Compounds specific for MC3-R or MC4-R, and particularly MC4-R, are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other treatment of food intake and metabolism-related disorders and conditions. Compounds specific for MC3-R and/or MC4-R, and particularly MC4-R, affect sexual response, and can be used as agents for treatment of sexual dysfunction, including male erectile dysfunction.
Most scientific investigators ascribe the sexual activity of melanotropin ligands to MC4-R. For example, see Van der Ploeg L H, Martin W J, Howard A D, Nargund R P Austin C P, Guan X, Drisko J, Cashen D, Sebhat I, Patchett A A, Figueroa D J, DiLella A G, Connolly B M, Weinberg D H, Tan C P, Palyha O C, Pong S S, MacNeil T, Rosenblum C, Vongs A, Tang R, Yu H, Sailer A W, Fong T M, Huang C, Tota M R, Chang R S, Stearns R, Tamvakopoulos C, Christ G, Drazen D L, Spar B D, Nelson R J, MacIntyre D E. A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 99:11381-6 (2002). Evidence in favor of this hypothesis comes from the fact that a sexual response elicited by an MC4-R agonist can be blocked by an MC4-R antagonist. However, a few reports also suggest that MC4-R receptors may not be involved in eliciting sexual function response (Vergoni A V, Bertolini A, Guidetti G, Karefilakis V, Filaferro M, Wikberg J E, Schioth H B. Chronic melanocortin 4 receptor blockage causes obesity without influencing sexual behavior in male rats. J Endocrino, 166:419-26 (2000)).
Because of the myriad biological effects of compounds specific for melanocortin receptors, there is a need for compounds and methods, including methods of selection of compounds, to differentiate the effects. More specifically, there is a need for compounds that effect a sexual response, by the same or similar regulatory pathways as those implicated in MC4-R-specific compounds, without eliciting other biological effects related to MC4-R, including without limitation energy homeostasis or feeding behaviors. For most pharmaceutical applications it is desirably to have a compound that is specific for a single biological effect, such as for example a compound that regulates and elicits a sexual response, and that is not substantially specific for MC4-R, is not an agonist or antagonist with respect to MC4-R, and that does not regulate energy homeostasis, such as by decreasing food intake and/or body weight or elicit or cause other responses characteristic of MC4-R specific molecules.